Process for producing an extract containing  tetrahydrocannabinol and cannabidiol from cannabis plant material, and cannabis extracts

ABSTRACT

The invention relates to a method for producing an extract from cannabis plant matter, containing tetrahydrocannabinol, cannabidiol and optionally the carboxylic acids thereof. According to said method, the dried plant matter is ground and subjected to a CO 2  extraction and the primary extract obtained is separated. The invention method permits Δ 8  or Δ 9  tetrahydrocannabinol to be selectively obtained both from industrial hemp and from drug-producing hemp, optionally after dissolving the primary extract in ethanol, separating undesirable waxes and removing the solvent under reduced pressure.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to a process for producing an extractcontaining tetra-hydrocannabinol, cannabidiol, and optionally thecarboxylic acids thereof from cannabis plant material in accordance withthe preamble of claim 1, a primary extract from cannabis plant materialin accordance with claim 8, and a process for producingtetrahydrocannabinol in accordance with claim 13 and a process forproducing cannabidiol in accordance with claim 14.

Cannabis (hemp), together with the genus Humulus (hops), belongs to thefamily of Cannabinaceae, with hops, for instance, not containing anycannabinoids. For the botanical and chemotaxonomical differentiation ofthe genus Cannabis there are two different concepts. One differentiatesbetween three species, Cannabis sativa Linnaeus, Cannabis indica LAM.,and Cannabis ruderalis, while a different theory only sees the existenceof the one collective species Cannabis sativa L. made up of thesubspecies Cannabis sativa ssp. sativa and ssp. indica. Moreover thecannabis plant is differentiated into a drug type and a fiber type, withdifferentiation being performed on the basis of the quantity ratio ofthe main cannabinoids, cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol(9-THC). Fiber hemp, whose cultivation is permitted for fiberproduction, must not exceed a Δ⁹-THC content of 0.3% relative to the dryplant mass, while the drug type may exhibit a Δ⁹-THC content of approx.5%-15% relative to the dry plant mass.

The ratio of Δ⁹-THC to CBD in fiber hemp is mostly less than 1.5. Thevarieties rich in Δ⁹-THC may reach a ratio of 2:1 to 7:1. Cannabissativa L. occurs worldwide in all warm and moderate zones with theexception of the humid tropical rain forests. It is an annual tobiennial, anemogamous herb which may attain a height of up to 8 m. Thedioecous, rarely monecious inflorescences contain the activecannabinoids in the resin which is mainly secreted by the numerousglandular bracts in the leaf axils. As a general rule, all the plantparts of Cannabis sativa L. with the exception of the seeds may containcannabinoids. The highest cannabinoid concentrations are found in thefloral bracts and fruit stalks. The leaves have a low content ofcannabinoids as a function of leaf age, while the stalk and particularlythe root exhibit clearly lower cannabinoid contents.

In Germany, the known cannabis preparations having a hallucinogeniceffect, marijuana and hashish, are subject to the regulations of theNarcotics Act as non-traffickable narcotics like opium, morphine,heroin, cocaine and LSD.

Cannabis sativa L. contains more than 420 different components, with 61compounds of these belonging to the class of cannabinoids. These arelipophilic, nitrogen-free, mostly phenolic compounds. The neutralcannabinoids are biogenetically derived from a monoterpene and a phenol,the acidic cannabinoids from a monoterpene and a phenolic acid, andpresent a C₂₁ parent substance. In literature, two different numberingsystems for cannabinoids are found. The older numbering system is basedon the monoterpene skeleton, whereas the more recent IUPAC designationwhich is exclusively employed in the present application, relates to thedibenzopyrane skeleton.

Among the most important cannabinoids there are:

Δ⁹-tetrahydrocannabinol Δ⁹-THC Δ⁸-tetrahydrorannabinol Δ⁸-THCcannabichromene CBC cannabidiol CBD cannabigerol CBG cannabinidiol CBNDcannabinol CBN

Besides the above mentioned cannabinoids, the associated carboxylicacids thereof are moreover found in the raw drug as well as in the plantproducts. As a general rule, the carboxylic acids have the function of abiosynthetic precursor. Thus, for instance, the tetrahydrocannabinolsΔ⁹- and Δ⁸-THC and CBD are generated in vivo from the THC carboxylicacids by decarboxylation from the associated cannabidiol carboxylicacids.

Δ⁸-THC may, for instance, also form upon cyclization of CBD. Anotherpossibility is that Δ⁸-THC may be generated under certain conditions,for instance acidity, by double bond isomerism from Δ⁹-THC or itscarboxylic acid, respectively.

In the following, the chemical structures of some cannabinoid activeprinciples and the nomenclature of the two active principles oftetrahydrocannabinol are specified, which bear the IUPAC names(6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-olor Δ⁹-THC, and(6aR-trans)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-olor Δ⁸-THC. Δ⁹-THC is also known under the designation of Dronabinol.

In the framework of the present invention, the expression“tetrahydrocannabinol” or “THC”—where not otherwise specified—is toencompass any isomers, in particular double bond isomers.

In many cultures and for a long time, cannabis has been a traditionaldrug and a remedy. Up into the 20th century, cannabis was employed forthe most variegated ailments—from asthma to migraine. Restrictivelegislation against cannabis on the part of the USA, however, broughtabout its complete disappearance from the pharmacopoeiae and fromphysicians' repertories of treatment.

In the meantime, many of the therapeutical effects handed down arecoming to be confirmed in clinical research. At present, thepharmacological use of cannabis active principles is of importanceessentially in the following indications:

-   -   the appetite stimulating effect, in particular in the case of        AIDS-related afflictions accompanied by cachexia and wasting        syndrome,    -   the antiemetic action for inhibiting nausea and vomiting,        particularly in connection with chemotherapy under        administration of cytostatic agents,    -   the reduction of muscle cramps and spasms in multiple sclerosis        and traverse lesions of the cord with paraplegia,    -   pain and migraine treatment—in chronic pain therapy also        complementarily with opioid treatment,    -   lowering intra-ocular pressure in glaucoma,    -   mood improvement,        and in particular cannabidiol as an anti-epileptic.

Owing to the interesting therapeutic range of the cannabinoids, a numberof experiments were carried out to enrich, isolate and/or synthesize thecannabinoids exclusively from drug hemp.

Thus, e.g., DE 41 00 441 A1 discloses a process for producing6,12-dihydro-6-hydroxy-cannabidiol and its use for producingtrans-Δ⁹-tetrahydrocannabinol. In particular DE 41 00 441 A1 describesthe manufacture of 6,12-dihydro-6-hydroxy-cannabidiol, which is obtainedby reacting olivetol and cis-p-menth-2-ene-1,8-diol, and its furtherreaction to trans-Δ⁹-tetrahydrocannabinol by using suitable catalysts.

A drawback of this prior-art process, however, is the relatively highexpenditure and the ultimately costly product obtained.

Apart from this, solvent extraction, e.g. with the aid of ethanol, andsteam distillation of cannabis constituents is known; in particular ahashish oil (cannabis resin extract) also referred to as Oil, Red Oil orIndian Oil is known, which is produced with the aid of solventextraction or distillation from cannabis herb or cannabis resin andwhich is a dark brown, viscous and sticky oil. The oil thus obtained issubsequently mostly diluted with edible oil for improved handling andcontains up to 65% of the hallucinogenic agent Δ⁹-THC (Kleiber/Kovar:Auswirkungen des Cannabiskonsums: Eine Expertise zu pharmakologischenand psychosozialen Konsequenzen, Stuttgart: Wiss. Verl.-Ges. 1998).

Dronabinol, Δ⁹-THC, has meanwhile been approved in the USA in accordancewith USP [United States Pharmacopoeia] 24, pp. 613, 614 as amedicament—also in capsule form—. In accordance with this monography,dronabinol contains no less than 95% of Δ⁹-THC and no more than 2% ofΔ⁸-THC.

As of Feb. 1, 1998, dronabinol may be prescribed as an anaesthetic inGermany.

WO 00/25127 A1 moreover relates to the extraction of hemp for theisolation of tetrahydrocannabinol from the natural cannabis plant. Whatis described in particular is an extraction process with an apolarorganic solvent, followed by fractional distillation under reducedpressure in order to produce distillates having hightetrahydrocannabinol contents. As suitable apolar solvents, loweralkanes such as, e.g., hexane, heptane or isooctane are named in WO00/25127 A1.

In accordance with Examples 1, 2, 3, 4 and 7 of reference WO 00/25127A1, exclusively drug hemp having tetrahydrocannabinol dry concentrationsof 2.20%-7.82% is extracted with hexane.

Such primary hexane extracts in accordance with WO 00/25127 A1 contain28.76% (Example 2) up to a maximum of 41.2% (Example 3) oftetrahydrocannabinol.

Apart from tetrahydrocannabinol, WO 00/25127 A1 does not disclose anyfurther constituents of the hexane primary extract.

Starting out from the above explained prior art and from the new legalsituation in the Federal Republic of Germany, it accordingly was theobject of the present invention to provide Δ⁹-tetrahydrocannabinol,Δ⁹-tetrahydro-cannabinol and cannabidiol in pure form and as an extractin the form of preparations for medical applications, wherein the activeprinciples should preferably be obtained from hemp varieties having lowcannabinoid contents for the reason of better availability.

In terms of process technology, this object is accomplished through thecharacterizing features of claims 1, 13 and 14. With regard to anextract having the main constituents Δ⁹-THC, Δ⁸-THC and CBD, the aboveobject is accomplished through the characterizing features of claim 8.

In accordance with the invention, a primary extract containingtetrahydrocannabinol, cannabidiol, and optionally the carboxylic acidsthereof, is obtained from cannabis plant material in that the driedplant material is comminuted, the plant material is extracted with theaid of CO₂ under supercritical pressure and temperature conditions at atemperature in the range of approx. 31° C. to 80° C. and at a pressurein the range of approx. 75 bar to 500 bar, or in the subcricital rangeat a temperature of approx. 20° C. to 30° C. and a supercriticalpressure of approx. 100 bar to 350 bar; or extracted under subcricitalpressure and temperature conditions; and the obtained primary extract isseparated under subcricital conditions, or under conditions that aresubcricital in terms of pressure and supercritical in terms oftemperature.

In terms of cannabinoids, the primary extract of the invention containshigh proportions of cannabidiol carboxylic acid (CBIS), cannabidiol(CBD), and Δ⁹-tetra-hydrocannabinol carboxylic acid (Δ⁹-THCS), andΔ⁹-THC (when drug hemp is used).

The production of CO₂ extracts is known in principle. Thus, e.g., DE 19800 330 A1 discloses the production of a pharmaceutically active extractfrom Tanacetum parthenium through CO₂ extraction with the aid of anextraction plant as used in the present invention.

As a particularly preferred cannabis plant material, for reasons ofprocurement on an industrial scale, one from Cannabis sativa L., inparticular hemp of the fiber type, i.e. so-called industrial hemp, isused.

Owing to currently valid legislation, industrial hemp species of thefiber type may contain 0.3% of Δ⁹-THC at maximum in the Federal Republicof Germany; for Switzerland an upper limit of 0.5% Δ⁹-THC applies, basedon the dry plant mass in either case.

The like industrial hemp varieties may be cultivated both in the FederalRepublic of Germany and in Switzerland, for example, while requiringneither any complicated cultivating permission nor any complicatedsafety installations during storage.

It is thus advantageous if cannabis plant material of the fiber type maybe used for the production of primary extracts containing Δ⁹-THC andCBD, for it is possible to employ such starting material having a lowΔ⁹-THC content for the inventive process without any further operatingand handling permissions as are required in the case of drug hemp types.

Varieties entering into consideration here are in particular the Frenchvarieties Fedora 19, Felina 45 and Futura 77, the Hungarian varietiesKompolti and Uniko-B and the Finnish variety Finola 314, for the averagefor all varieties lies clearly below the specified limits (Mediavilla,V. and Brenneisen, R. 1996: Mitt. Ges, Pflanzenbauwiss. 9: 243-244).

When it is possible to employ drug hemp types, however, the Δ⁹-THCcontent in the primary extract is higher than in one produced of fiberhemp.

The addition to the CO₂ of an entraining agent selected from the groupconsisting of: propane, butane, ethanol and water, has the advantagethat hereby the yields for Δ⁹-THC and CBD may be increased withoutinvolving the drawbacks as with an extract produced, e.g., with ethanolor ethanol/water or methanol/chloroform or with other chlorinatedhydrocarbons.

Typically the entraining agent concentrations are in the range of 1-10%based on the employed quantity of CO₂.

The extraction process of the invention preferably operates in thesupercritical range at a temperature of approx. 31° C. to 80° C. and apressure of approx. 75 bar to 500 bar, in particular at a temperature ofapprox. 45° C. to 65° C. and a pressure of approx. 100 bar to 350 bar,preferably at a temperature of approx. 60° C. and a pressure of approx.250 bar.

In the subcricital range, in contrast, a temperature of approx. 20° C.to 30° C. and a supercritical pressure of approx. 100 bar to 350 bar areused.

The measure of arranging a layer of adsorbent on the material to beextracted downstream relative to the CO₂ flow has the advantage thatmonoterpenes and sesquiterpenes as well as alkaloids, flavonoids andchlorophylls may be separated out, so that the inventive primaryextracts are even the more superior to the ethanol extracts known in theprior art and to the extracts prepared with the aid of chlorinatedhydrocarbons, for the latter in any case are fairly high in mono- andsesquiterpenes as well as chlorophylls, flavonoids and alkaloids.

As an alternative, the CO₂ laden with THC and CBD as well as withproportions of reduced mono- and sesquiterpenes, flavonoids,chlorophylls and alkaloids may also be passed over adsorbers chargedwith adsorbents or separators (FIG. 1).

Preferred adsorbents are those selected from the group comprised of:silica gel, diatomaceous earth, bentonites, bleaching earth, activatedcarbons, in particular magnesium oxide and alumina, as well as mixturesthereof.

In order to increase the extraction yield, it is preferred to repeatextraction at least once, with extraction preferably being repeated withdiatomaceous earth and/or some other adsorbent.

The inventive primary extracts from Cannabis plant material containingΔ⁹-THC and cannabidiol are substantially free from monoterpenes andsesquiterpenes and moreover free from alkaloids and flavonoids, andcontain practically no chlorophylls.

Where a hemp of the drug type is used as a starting material, Δ⁹-THC isthe main constituent of the primary extract, and CBD the second highestproportion.

Where, however, a hemp of the fiber type is used as a starting material,which is being preferred, CBD and in a given case the carboxylic acidsthereof are found as the main constituents of the primary extract.

The primary extract of the invention contains at least reducedproportions of monoterpene and sesquiterpene hydrocarbons, alkaloids,flavonoids and chlorophylls, and is preferably already free from thesecomponents, in particular from alkaloids, flavonoids and chlorophylls.

Where undesirable waxes are present in certain industrial and drug hempvarieties, these are purified after completed primary extraction anddecarboxylation by subsequent dissolution of the primary extract, e.g.in cold (20° C.) ethanol or ethanol solution, and separated from thenon-dissolved wax by filtration. The filtration residue amounts toapproximately 3-5%. In order to obtain the purified extract, thesolvent, e.g. ethanol, is again removed under reduced pressure.

In order to obtain Δ⁹-THC and CBD from the primary extract thuspurified, the cannabidiol carboxylic acids and Δ⁹-tetrahydrocannabinolcarboxylic acids contained in the primary extract are decarboxylatedinto cannabidiol and Δ⁹-tetrahydrocannabinol through increase intemperature.

Where Δ⁹-THC is to be obtained as the main constituent or in pure form,the CBD may be reacted into Δ⁹-THC through catalyzed cyclization.

Here a Δ⁸-THC may form depending on process conditions, which in itselfalso possesses interesting pharmacological properties. Thus Δ⁸-THC may,for example, be employed as an antiemetic in pediatric oncology.

Where the primary extract was obtained from fiber hemp and the entireCBD is to be transformed to Δ⁸-THC and Δ⁹-THC, cyclization into Δ⁸-THCand Δ⁹-THC takes place during preparation of the secondary extract.Cyclization takes place under the following conditions:

The decarboxylated primary extract is mixed with a water-binding agentand a catalyst defined more closely hereinbelow. The mixture is treatedin a high-pressure extraction plant (FIG. 2) with supercritical CO₂,preferably at 300 bar and 70° C. By this treatment, the CBD present inthe primary extract is substantially reacted to Δ⁸-THC and Δ⁹-THC.

The obtained extract is separated out under pressure and temperatureconditions subcricital for CO₂, preferably at approx, 55 bar and approx.25° C.

As a water-binding agent zeolitic molecular sieves having a pore size of3-10 Å, preferably 5 Å may be used, and useful catalysts aremetal-containing halogen salts containing the metals tin, zinc, iron ortitanium, preferably zinc chloride.

The secondary extract thus obtained only contains very little CBD and ishighly enriched in Δ⁸-THC and Δ⁹-THC.

Suitably for obtaining pure or nearly pure Δ⁹-THC or Δ⁸-THC,respectively, a treatment in a high-pressure apparatus withsupercritical CO₂ is performed as described in the following (FIG. 3).

To this end, preferably a high-pressure column (FIG. 3) subdivided intosegments, comprising a bottom segment for dissolving the primary extractin supercritical CO₂, a purification segment filled, e.g., with silicagel (mean particle size of 0.02 mm to 0.2 mm, preferably 0.1 mm), a headsegment for discharging the mixture dissolved in supercritical CO2 ofCBD, Δ⁸-THC and Δ⁹-THC into three separating vessels for separateseparation of the purified CBD and the purified Δ⁸-THC and Δ⁹-THC.

The extraction conditions prevailing for purification in the column aresupercritical for CO₂, preferably 180 bar and 55° C., in the firstseparating vessel where CBD is separated out for CO₂ subcricitalconditions in terms of pressure and supercritical conditions in terms oftemperature, preferably 70 bar and 50° C. In the second and thirdseparating vessels, where Δ⁸-THC and Δ⁹-THC are separated out,conditions subcricital for CO₂ in terms of pressure and temperature areto prevail, in the second separating vessel preferably 60 bar and 30°C., in the third separating vessel preferably 55 bar and 25° C.

If fiber hemp is used, it may possibly be necessary to further purifythe tetrahydrocannabinol products Δ⁸-THC and Δ⁹-THC thus obtained withthe aid of additional processes such as preparative chromatography orHPLC.

Where the primary extract was obtained from drug hemp and purified CBDis furthermore desired as an end product besides purified Δ⁹-THC, thecyclization of CBD into Δ⁸-THC and Δ⁹-THC, or the production of asecondary extract is omitted. Δ⁸-THC is an isomer of Δ⁹-THC and formssubstantially during the cyclization of CBD to Δ⁹-THC as well as in thepresence of acids. Under certain circumstances it is necessary for theΔ⁸-THC, Δ⁹-THC and CBD thus obtained to be purified by further processessuch as preparative chromatography or HPLC.

The reaction scheme of these reactions is given below:

As may be seen from the scheme of formulae, Δ⁹-THC may under the actionof acids isomerize to Δ⁸-THC.

As cannabidiol taken for itself has interesting pharmacologicalproperties while furthermore lacking the psychotropic hallucinogeniceffect of Δ⁹-THC, cannabidiol itself is also of interest for practicalapplication because it may be used, e.g., as an anti-epileptic.

Cannabidiol may be obtained in accordance with the inventive process ofclaim 15.

Δ⁸-THC by itself also has substantially lower psychotropichallucinogenic effects than Δ⁹-THC and may be obtained in accordancewith claim 14.

BRIEF DECRIPTION OF THE DRAWINGS

Further advantages and features of the present invention result from thedescription of practical examples and from the drawings, wherein:

FIG. 1 is a schematic representation of a CO₂ extraction plant forproducing the primary extract of the invention;

FIG. 2 is a schematic representation of a CO₂ extraction plant forproducing a secondary extract highly enriched in Δ⁸-THC and Δ⁹-THC; and

FIG. 3 is a schematic representation of a CO₂ extraction plant forseparation of a primary and/or secondary extract in CBD, optionallyΔ⁸-THC and Δ⁹-THC in a high-pressure column.

DETAILED DESCRIPTION OF THE INVENTION

Ground Cannabis plant material comprised substantially of inflorescencesand leaves is charged into extracting vessels 1-4. CO₂ having beenbrought to a temperature of approx. 60° C. and to a pressure of approx.250 bar, enters into contact with the material to be extracted in theextracting vessels 1-4 and extracts the desired cannabinoid components,in particular comprising Δ⁹-tetrahydrocannabinol and cannabidiol as wellas the carboxylic acids thereof. Suitably for extraction a flow rate of50-150 kg of CO₂/kg of starting material is used.

At the upper end of extracting vessel 4, an extract enriched in thecannabinoids leaves the vessel via conduit 6 a and arrives at the bottomof separating vessel 5 a. The separating vessels 5 a and 5 b are in theexemplary case filled with various zeolitic molecular sieves and withdiatomaceous earth as an adsorbent. In separating vessels 5 a and 5 b,the same pressure and temperature conditions prevail as in extractingvessels 1-4. The zeolitic molecular sieves placed in container 6 a havean internal surface of approx. 800 m²/g, the zeolitic molecular sievesplaced in container 6 b have an internal surface of approx. 1200 m²/g.

By charging containers 6 a and 5 b with molecular sieves—preferred,however not indispensable—alkaloids, flavonoids and chlorophylls arefurther separated from the CO₂ loaded with extract. This CO₂ extractionmixture thus purified exits from the head of vessel 5 b via conduit 7,pressure regulation valve 8, with extraction pressure being reduced toless than 75 bar, in the exemplary case to approx. 60 bar. The CO₂extract mixture then arrives at heat exchanger 9 where it is heated to atemperature supercritical for CO₂, preferably to 45° C.

Under these pressure and temperature conditions, extraction of thatextract portion takes place in the separating vessel 10 whichessentially still contains undesirable monoterpenes and sesquiterpenes.The extract mixture consisting of CO₂ and essentially of Δ⁹-THC andcannabidiol as well as the carboxylic acids thereof, exits fromseparating vessel 10 via conduit 11, pressure regulation valve 12, heatexchanger 13, and finally is conveyed into separating vessel 14.

With the aid of pressure regulation valve 12, the separation pressure incontainer 14 is set to pressure conditions subcricital for CO₂, in theexemplary case 50 bar. The separation temperature in vessel 14 iscontrolled by heat exchanger 13 to a temperature subcricital for CO₂, inthe exemplary case about 20° C. Under these conditions the pure CO₂ isseparated from the primary extract enriched in g-THC and cannabidiol andthe carboxylic acids thereof in separating vessel 14.

The pure CO₂ is conveyed via conduit 15 to liquefier 17 that is equippedwith a condenser coil 16. From here the liquid CO₂ is supplied viapressurizing pump 18 to heat exchanger 19, to be available for thefollowing extraction cycle.

For opening the extracting vessel, i.e. for charging and emptying thevessels with, or of, the starting material, the CO₂ is either venteddirectly via conduit 21, or supplied via conduit 20 to recycling plant22 which then pumps the liquid CO₂ into the CO₂ storage vessel 23.

FIG. 2 shows a schematic representation of a CO₂ extraction plant forproducing a secondary extract highly enriched in Δ⁸-THC and Δ⁹-THC.

For the reaction, in particular the decarboxylation, of the cannabinoidcarboxylic acids contained in the primary extract into Δ⁹-THC and CBD,the primary extract in the exemplary case is treated during about 2hours at 80° C.

A mixture of decarboxylated primary extract, water-binding agent andcatalyst is introduced into the extracting vessel 200. CO₂ at atemperature of 70° C. and a pressure of 300 bar enters into contact withthe material to be extracted and extracts the desired components.

Following cyclization, the secondary extract highly enriched in Δ⁸-THCand Δ⁹-THC exits from vessel 200 at the top end of extracting vessel 200via conduit 202 and arrives in separating vessel 205 via regulatingvalve 203—wherein pressure is reduced to 60 bar or 55 bar,respectively—and heat exchanger 204, the temperature being 30° C. or 25°C., respectively. Through valve 206 the secondary extract thus obtained,which contains small amounts of CBD and is highly enriched in Δ⁸-THC andΔ⁹-THC, may be withdrawn from separating vessel 205.

The pure CO₂ is conveyed via conduit 207 to liquefier 208 which isequipped with a condenser coil 209. From there the liquid CO₂ issupplied via pressurizing, pump 210 to heat exchanger 211, to beavailable for the following extraction cycle.

FIG. 3 shows a schematic representation of a CO₂ extraction plant forseparation of a primary and/or secondary extract CBD, optionally Δ⁸-THCand Δ⁹-THC, in a high-pressure column.

Via extraction column 300 wherein an extraction pressure of 180 bar anda temperature of 55° C. prevail, consisting of bottom segment 301 a,purification segment 301 b (charged with silica gel) and head segment301 c, the extract mixture dissolved in CO₂ arrives via duct 302,regulating valve 303 and heat exchanger 304 in separating vessel 305,where preferably a pressure of 70 bar and a temperature of 50° C. are toprevail. It is here that the CBD is obtained.

Via duct 307, regulating valve 308 and heat exchanger 309 the extractionmixture arrives in the second separating vessel 310, preferably with apressure of 60 bar and a temperature of 30° C. prevailing. It is herethat the separation of Δ⁸-THC takes place. Via valve 311 the obtainedΔ⁸-THC may be withdrawn.

The Δ⁹-THC still dissolved in CO₂ is transferred into separating vessel315 via duct 312, regulating valve 313 and heat exchanger 314. There itis separated out under a pressure of preferably 55 bar and a temperatureof preferably 25° C. Via valve 316 the obtained Δ⁹-THC may be withdrawn.

The pure CO₂ is conveyed via conduit 317 to liquefier 318 which isequipped with a condenser coil 319. From here the liquid CO₂ is suppliedvia pressurizing pump 320 to heat exchanger 321, to be available for thefollowing extraction cycle.

Modifications in the described plant systems are very well possiblewithout the scope of the invention being restricted thereby.

As industrial hemp of the fiber type, in the present exemplary case theFrench Cannabis sativa variety Fedora 19 is employed. The raw drug hasan average content of approx. 0.25% of Δ⁹-THC and 1.54% of CBD.

As a result, a primary extract having the properties indicated in Table1 is obtained.

TABLE 1 Primary extracts from industrial hemp with different solventsEtOH Hexane primary Inventive Measured primary extract* in accordanceprimary CO₂ substance extract with WO00/25127 extract Chlorophyll 3.00%2.85% 0.010% CBD 14.50%  12.40%  58.000%  Δ⁹-THC 2.30% 2.30% 9.500%Δ⁸-THC 0.00% 0.00% 0.000% CBN 0.50% 0.50% 0.100% Flavonoid 12.50%  8.50%0.150% glycosides Alkaloids: 0.20% 0.35% 0.001% cannabisativinMonoterpenes: α-Pinene 0.02% 0.03% 0.001% β-Pinene 0.01% 0.02% 0.001%Myrcene 0.02% 0.02% 0.001% Sesquiterpenes: Caryophyllene 0.53% 0.45%0.020% β-Humulene 0.18% 0.22% 0.008% Δ-Selinene 0.10% 0.15% 0.004% *This column relates to a test comparing the CO₂ extracts in accordancewith the present invention with the prior-art hexane extracts ofWO00/25127 as discussed at the outset. An industrial hemp having thefollowing raw drug data: water content: 11.2% (wt.); Δ⁹-THC 0.25% (wt.);and CBD: 1.54% were extracted with hexane in accordance with WO00/25127.To this end, 100 g of air-dried, pulverized industrial hemp wasextracted for 24 hours in 4 I of hexane in accordance with the Soxhletmethod. The solvent was removed under reduced pressure, and the obtainedextract was analyzed with a view to the parameters indicated in Table 1.

When one compares the data of the CO₂ primary extract in accordance withthe present invention as shown in Table 1 with the hexane extract inaccordance with WO00/25127 and the ethanol extract, initially therelatively good coincidence of the primary extracts obtained by means ofthe organic solvents is conspicuous.

Moreover in comparison with the CO₂ primary extract of the presentinvention, there results a disadvantageously high chlorophyll content of3.00% for the hexane extract and of 2.85% for the ethanol extract. Forthe extract of the invention, the chlorophyll content thus is lower by afactor of almost 300 than in the prior-art extracts.

A low chlorophyll content is particularly advantageous because undercertain circumstances, such as when a soft gelatin is used forencapsulation of the extract in the framework of galenic formulation,chlorophyll may involve cross-reticulations which may prevent the activeprinciples contained in the extract from being released.

The desired CBD content is in the inventive CO₂ extract higher by afactor 4 to 5, and the Δ⁹-THC content also by a factor >4, in comparisonwith the prior-art solvent extracts.

If one regards the overall cannabinoid content, essentially composed ofCBD, Δ⁹-THC and CBN, it may be seen that even the inventive primary CO₂extract already is made up at more than two thirds of theseconstituents, whereas the prior-art extracts only contain an overallcannabinoid content of approx. 15 to 17%.

Moreover what is conspicuous in comparison with the extract of theinvention are the highly elevated (more than 80-fold) flavonoidglycoside contents of the ethanol and hexane extracts.

The detected terpene and alkaloid quantities are also strongly elevatedin comparison with the extracts according to the invention:

The contents of undesirable monoterpenes listed in Table 1 are higher bya factor of 10-30 than in the two primary extracts obtained with ethanoland hexane than in the CO₂ primary extract, and while the sesquiterpenecontent is higher by a factor 20 to 40 than in the inventive CO₂extracts.

It is moreover noted that the primary extracts obtained with the aid oflipophilic solvents contain the alkaloids that are readily soluble inthese solvents, such as, e.g., cannabisativin which is highly cytotoxic.This alkaloid contamination may very well also still occur in an extractprepared in accordance with WO00/25127 from the primary extractdescribed there, following additional purification and enrichment stepsin accordance with WO00/25127 which extract is said to have a 98%content of Δ⁹-THC.

In contrast, already the primary extracts of the invention without anyfurther purification steps—as shown in Table 1—practically do notcontain any more cannabisativin.

Thus the ethanol extract contains about 200 times more toxic alkaloids,in particular the highly cytotoxic cannabissativin, and the hexaneextract in accordance with WO00/25127 even about 350 times more than theCO₂ primary extract of the invention.

Thus the CO₂ extracts of the present invention are superior both to thehexane extracts in accordance with WO00/25127 and to the customaryethanol extracts, because of their high cannabinoid contents and thefact that they are largely free from alkaloids, flavonoid glycosides,mono- and sesqiterpenes.

What is particularly advantageous is the circumstance that the presentinvention starts out from a hemp having a THC proportion near Zero,which is not even the case in WO00/25127 as this reference starts outfrom higher THC concentrations in the raw drug inasmuch as drug hemp,not industrial hemp is extracted there.

In view of this very fact it thus is already surprising that THC andcannabinoids may at all be enriched in technically useful amounts fromreadily available industrial hemp by means of CO₂ extraction.

Table 2 shows the components of a secondary extract after completedanellation.

TABLE 2 Secondary extract following cyclization (FIG. 2) CO₂ secondaryextract  P₁ = 300 bar T₁ = 70° C. P₂ = 55 bar Measured substance T₂ =25° C. Chlorophyll 0.01% CBD  1.5% Δ⁹-THC 41.2% Δ⁸-THC 24.3% CBN  0.1%

Table 3 shows the components of a primary extract purified byhigh-pressure column in accordance with FIG. 3.

TABLE 3 Purified primary extract afterchemical purification in ahigh-pressure column (FIG. 3) Purified primary extract  P₁ = 180 bar T₁= 55° C. P₂ = 70 bar (separating vessel No. 5)  T₂ = 50°   P₃ = 60 bar(separating vessel No. 10) T₃ = 30° C. P₄ = 55 bar (separating vesselNo. 15) Measured T₄ = 25° C. substance Separator No. 5 Separator No. 10Separator No. 15 Chlorophyll 0.01% 0.01% 0.01% CBD 85.0%  0.0%  1.5%Δ⁹-THC  2.0%  0.0% 87.0% Δ⁸-THC  0.0%  0.0%  0.0% CBN  0.1%  0.1%  0.1%

Table 4 shows the components of a secondary extract which was purifiedin a high-pressure column.

TABLE 4 Purified secondary extract following purification in ahigh-pressure column (FIG. 3) Purified secondary extract P₁ = 180 bar T₁= 55° C. P₂ = 70 bar (separating vessel No. 5) T₂ = 50° C. P₃ = 60 bar(separating vessel No. 10) T₃ = 30° C. P₄ = 55 bar (separating vesselNo. 15) Measured T₄ = 25° C. substance Separator No. 5 Separator No. 10Separator No. 15 Chlorophyll 0.01%  0.01%  0.01%  CBD 90.0%  0.1% 0.3%Δ⁹-THC 0.5% 1.0% 96.0%  Δ⁸-THC 0.2% 85.0%  1.5% CBN 0.1% 0.1% 0.1%

It is, of course, fundamentally also possible to use a drug hemp forcarrying out the process of the invention.

The above mentioned primary extract is treated further in accordancewith the description in FIG. 2 and FIG. 3 and is suited as an activeprinciple for the production of a medicament for the indicationsdescribed at the outset.

Suitable application types are inhalation, oral, parenteral, as well asenteral application.

1.-14. (canceled)
 15. A process for producing an extract containingtetrahydrocannabinol and/or cannabidiol, and optionally the carboxylicacids thereof, from a cannabis plant material, the process comprising:(1) subjecting the cannabis plant material to CO₂ (1a) undersupercritical pressure and temperature conditions at a temperature in arange of approx. 31° C. to 80° C. and at a pressure in a range ofapprox. 75 bar to 500 bar; (1b) in liquefied form in the subcriticalrange at a temperature of approx. 20° C. to 30° C. and a supercriticalpressure of approx. 100 bar to 350 bar; or (1c) in liquefied form undersubcritical pressure and temperature conditions; to extract cannabinoidcomponents; and (2) reducing the temperature and/or pressure to separatetetrahydrocannabinol and/or cannabidiol, and optionally the carboxylicacids thereof, from the CO₂, to form an extract.
 16. The process ofclaim 15, wherein in step (1) the CO₂ is under supercritical pressureand temperature conditions at a temperature in a range of approx. 31° C.to 80° C. and at a pressure in a range of approx. 75 bar to 500 bar. 17.The process of claim 16, wherein in step (1) the CO₂ is at a temperaturein a range of approx. 45° C. to 65° C. and at a pressure in a range ofapprox. 100 bar to 350 bar.
 18. The process of claim 16, wherein in step(1) the CO₂ is at a temperature of approx. 60° C. and at a pressure ofapprox. 250 bar.
 19. The process of claim 16, wherein in step (1) theCO₂ is at a temperature of approx. 55° C. and at a pressure of approx.180 bar.
 20. The process of claim 15, wherein in step (1) the CO₂ is inliquefied form in the subcritical range at a temperature of approx. 20°C. to 30° C. and a supercritical pressure of approx. 100 bar to 350 bar.21. The process of claim 15, wherein in step (1) the CO₂ is in liquefiedform under subcritical pressure of less than 70 bar and subcriticaltemperature of less than 30.0° C.
 22. The process of claim 21, whereinin step (1) the CO₂ in liquefied form is at a pressure of about 60 bar.23. The process of claim 21, wherein in step (1) the CO₂in liquefiedform is at a temperature of less than 20.0° C.
 24. The process of claim16, wherein in step (2) the CO₂ is under conditions supercritical intemperature and subcritical in pressure.
 25. The process of claim 24,wherein in step (2) the CO₂ is at a pressure of about 75 bar or less.26. The process of claim 25, wherein in step (2) the CO₂ is at atemperature of between about 45° C. to about 55° C.
 27. The process ofclaim 15, wherein in step (2) the CO₂ is under subcritical pressure andtemperature conditions.
 28. The process of claim 27, wherein in step (2)the CO₂ is at a pressure of about 60 bar or less.
 29. The process ofclaim 28, wherein in step (2) the CO₂ is at a temperature of about 30°C. or less.
 30. The process of claim 28, wherein in step (2) the CO₂ isat a temperature of about 20° C. or less.
 31. The process of claim 15,further comprising a step of decarboxylating the carboxylic acids oftetrahydrocannabinol and cannabidiol in the plant material.
 32. Theprocess of claim 15, further comprising a step of subjecting the extractof step (2) to cold ethanol or ethanol solution to precipitate waxes,separating the precipitated waxes by filtration, and then removing theethanol or ethanol solution.
 33. The process of claim 15, furthercomprising subjecting the CO₂ extracted from step (2) to increasedpressure and temperature and recycling said CO₂ to step (1).
 34. Theprocess of claim 15, wherein the cannabis plant material contains 0.5%or less of Δ⁹-THC based on the dry plant mass.
 35. A process forproducing an extract containing tetrahydrocannabinol and/or cannabidiol,and optionally the carboxylic acids thereof, from a cannabis plantmaterial, the process comprising: (1) subjecting the cannabis plantmaterial to CO₂ under supercritical pressure and temperature conditionsat a temperature in a range of approx. 31° C. to 80° C. and at apressure in a range of approx. 75 bar to 500 bar, to extract cannabinoidcomponents; (2) reducing the temperature and/or pressure to separatetetrahydrocannabinol and/or cannabidiol, and optionally the carboxylicacids thereof, from the CO_(2,) to form an extract; and (3) subjectingthe extract of step (2) to cold ethanol or ethanol solution toprecipitate waxes, separating the precipitated waxes by filtration, andthen removing the ethanol or ethanol solution.
 36. A process forproducing an extract containing tetrahydrocannabinol and/or cannabidiol,and optionally the carboxylic acids thereof, from a cannabis plantmaterial, the process comprising: (1) subjecting the cannabis plantmaterial to CO₂ in liquefied form in the subcritical range at atemperature of approx. 20° C. to 30° C. and a supercritical pressure ofapprox. 100 bar to 350 bar, to extract cannabinoid components; (2)reducing the temperature and/or pressure to separatetetrahydrocannabinol and/or cannabidiol, and optionally the carboxylicacids thereof, from the CO₂, to form an extract; and (3) subjecting theextract of step (2) to cold ethanol or ethanol solution to precipitatewaxes, separating the precipitated waxes by filtration, and thenremoving the ethanol or ethanol solution.